Introduction: Our understanding of how comorbid diseases influence health-related quality of life (HRQL) in patients with chronic obstructive pulmonary disease (COPD) is limited and in need of improvement. The aim of this study was to examine the associations between comorbidities and HRQL as measured by the instruments EuroQol-5 dimension (EQ-5D) and the COPD Assessment Test (CAT). Methods: Information on patient characteristics, chronic bronchitis, cardiovascular disease, diabetes, renal impairment, musculoskeletal symptoms, osteoporosis, depression, and EQ-5D and CAT questionnaire results was collected from 373 patients with Forced Expiratory Volume in one second (FEV1) <50% of predicted value from 27 secondary care respiratory units in Sweden. Correlation analyses and multiple linear regression models were performed using EQ-5D index, EQ-5D visual analog scale (VAS), and CAT scores as response variables. Results: Having more comorbid conditions was associated with a worse HRQL as assessed by all instruments. Chronic bronchitis was significantly associated with a worse HRQL as assessed by EQ-5D index (adjusted regression coefficient [95% confidence interval] –0.07 [–0.13 to –0.02]), EQ-5D VAS (–5.17 [–9.42 to –0.92]), and CAT (3.78 [2.35 to 5.20]). Musculoskeletal symptoms were significantly associated with worse EQ-5D index (–0.08 [–0.14 to –0.02]), osteoporosis with worse EQ-5D VAS (–4.65 [–9.27 to –0.03]), and depression with worse EQ-5D index (–0.10 [–0.17 to –0.04]). In stratification analyses, the associations of musculoskeletal symptoms, osteoporosis, and depression with HRQL were limited to female patients. Conclusion: The instruments EQ-5D and CAT complement each other and emerge as useful for assessing HRQL in patients with COPD. Chronic bronchitis, musculoskeletal symptoms, osteoporosis, and depression were associated with worse HRQL. We conclude that comorbid conditions, in particular chronic bronchitis, depression, osteoporosis, and musculoskeletal symptoms, should be taken into account in the clinical management of patients with severe COPD.